Synthesis of substituted 1,4-dihydropyridines in water using phase-transfer catalyst under microwave irradiation

Article abstract of DOI:10.1081/SCC-200039409

The synthesis of various substituted 1,4-dihydropyridines has been achieved by the reaction of aldehydes, ethyl/methyl acetoacetates, and ammonium acetate in water using phase-transfer catalyst under microwave irradiation. Compared to the classical Hantzsch's reaction conditions, this new method consistently has the advantage of good yields and short reaction times. Bifunctional compounds containing two units have been synthesized using dialdehyde as precursor in good yields.

Full text of DOI:10.1081/SCC-200039409

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Synthesis of Substituted
1,4‐Dihydropyridines in Water
Using Phase‐Transfer Catalyst
Under Microwave Irradiation
Hojatollah Salehi a b & Qing‐Xiang Guo a
a Department of Chemistry, University of Science
and Technology of China, 96‐JinZhai Rd, Hefei,
China
b Ministry of Science, Research and Technology,
P.O. Box 15875–6186, Tehran, Iran
Available online: 10 Jan 2011
To cite this article: Hojatollah Salehi & Qing‐Xiang Guo (2004): Synthesis of
Substituted 1,4‐Dihydropyridines in Water Using Phase‐Transfer Catalyst Under
Microwave Irradiation, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 34:23, 4349-4357
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 23, pp. 4349–4357, 2004
Synthesis of Substituted
1,4-Dihydropyridines in Water Using
Phase-Transfer Catalyst Under
Microwave Irradiation
Hojatollah Salehi1,2 and Qing-Xiang Guo1,
*
1Department of Chemistry, University of Science and Technology of
China, Hefei, China
2Ministry of Science, Research and Technology, Tehran, Iran
ABSTRACT
The synthesis of various substituted 1,4-dihydropyridines has been
achieved by the reaction of aldehydes, ethyl/methyl acetoacetates,
and ammonium acetate in water using phase-transfer catalyst under
microwave irradiation. Compared to the classical Hantzsch’s reaction
conditions, this new method consistently has the advantage of good
yields and short reaction times. Bifunctional compounds containing
*
Correspondence: Qing-Xiang Guo, Department of Chemistry, University of Science
and Technology of China, 96-JinZhai Rd, Hefei 230026, China; Fax: 86-551-
3606689; E-mail: qxguo@ustc.edu.cn.
4349
DOI: 10.1081/SCC-200039409
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4350
Salehi and Guo
two units have been synthesized using dialdehyde as precursor in good
yields.
Key Words: Dihydropyridines; Phase-transfer catalyst; Microwave
irradiation; Hantzsch’s reaction.
INTRODUCTION
It is well known that 1,4-dihydropyridines are an important class of
calcium channel blockers and have emerged as one of the most important
classes of drugs for the treatment of cardiovascular diseases, including
hypertension.[1] The dihydropyridin heterocyclic ring is a common feature
of various bioactive compounds such as vasodilator, bronchodilator, anti-
atherosclerotic, antitumor, geroprotective, heptaprotective, and antidiabetic
agents.[2–5] These examples clearly demonstrate the remarkable potential of
novel dihydropyridin derivatives as a source of valuable drug candidates.
The preparation of 1,4-dihydropyridines by classical Hantzsch syn-
thesis,[6] a one-pot condensation of an aldehyde with alkyl acetoacetate and
ammonia, was developed more than 100 years ago. When sterically hindered
aldehydes are employed in classical Hantzsch synthesis, extended reaction
times are needed, and still the yields are generally low.[7,8] Thus, Hantzsch’s
reaction for the synthesis of dihydropyridines has received renewed interest,
and several improved procedures have recently been reported.[9–13] Yields
have been improved compared to the original procedure by using a mixture
of the three starting materials in acetonitrile in the presence of TMSCI/
NaI.[9] Watanabe et al. improved the yields with the use of an autoclave.[10]
The drawback was extended reaction times compared to conventional
heating. The microwave-promoting Hantzsch’s reaction has also been
reported.[11–13]
However, in spite of their potential utility, many of these methods involve
expensive reagents, organic solvent, long reaction times, and unsatisfactory
yields. Thus, the development of an efficient and versatile method for the
preparation of Hantzsch’s reaction is an active ongoing research area, and
there is scope for further improvement toward milder reaction conditions,
low reaction times, and improved yields. Recently, the synthesis of some
1,4-dihydropyridines using ethanol as a solvent under microwave irradiation
was reported.[11] One of the serious constraints in the use of microwave
ovens in organic synthesis has been the selection of solvent for the reaction,
due to the possible loss of the solvent and volatile reactants, apart from fire
hazards. Hence, we thought that the water could be a safe alternative to
organic solvents in such reactions.

1,4-Dihydropyrdines
4351
Water is a cheap, readily available nontoxic solvent for use in chem-
istry.[14,15] There are, however, problems with the use of water, such as
solubility of substrates in water, but these problems have, to some extent,
been overcome by the use of phase-transfer catalysts and the design of
novel heterogeneous catalysts.[16,17] Application of microwave irradiation in
organic synthesis is becoming an increasingly popular technology because
of its rapid reaction rate, cleaner reaction condition, and ease of manipu-
lation.[18–21] With its high dielectric constant, water is also, potentially,
a very useful solvent for microwave-mediated synthesis.[18–21]
We report here, the synthesis of 1,4-dihydropyridines in water using
phase-transfer catalyst under microwave irradiation. The Hantzsch ester syn-
thesis was carried out in a modified microwave oven by reacting ethyl/methyl
acetoacetate with an aldehyde and ammonium acetate using tetrabutyl
ammonium bromide as a phase-transfer catalyst in water (Scheme 1).
In order to improve the yields, we performed reactions using different
quantities of reagents. The best results were obtained with a 1 : 2 : 2 : 0.5 of
aldehyde, ammonium acetate, and ethyl/methyl acetoacetate and tetra-
butyl ammonium bromide. As can be seen from Table 1, aldehydes, ethyl/
methyl acetoacetates, and ammonium acetate in the presence of tetrabutyl
ammonium bromide as phase-transfer catalyst in water gave the corresponding
1,4-dihydropyridines under microwave irradiation in good yields after
several minutes. A variety of substituted aromatic, aliphatic, and heterocyclic
aldehydes carrying either electron-donating or electron-withdrawing sub-
stituents afford high yields of products. The procedure avoids problems
associated with organic solvent use (cost, handling, safety, and pollution).
Another important aspect is that various functionalities, such as hydroxy,
halide, nitro, and ether, survived under the present reaction conditions.
Aqueous ammonium hydroxide used by the previous authors[12] was replaced
with ammonium acetate in the present investigation, which might have
enhanced the yields. The loss of ammonia during heating could be minimized
by using ammonium acetate, thereby improving the yields. All the reactions
Scheme 1.

4352
Salehi and Guo
Table 1. Synthesis of substituted 1,4-dihydropyridines in water using phase-transfer
catalyst under microwave irradiation.
Entry
R1
R2
Product
Time (min)
Yield (%)a
1
2
C6H5
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
4a
4b
4c
4d
4e
4f
10
10
10
10
5
85
82
80
88
91
77
81
79
81
86
91
85
86
81
83
80
89
79
92
78
82
3-(NO2)-C6H4
4-(OMe)-C6H4
4-(Cl)-C6H4
2-Furyl
3
4
5
6
2,4-(Cl)2-C6H3
4-(OH)-C6H4
2-(Cl)-C6H4
4-(Me)-C6H4
C6H5CH55CH
H
10
10
10
10
5
7
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
4j
4k
4l
3
Me
n-C3H7
10
5
4m
4n
4o
4p
4q
4r
4s
(CH3)2CH-CH2
C6H5
10
10
10
5
3-(NO2)-C6H4
2-Furyl
Me
OEt
OEt
OEt
OEt
10
3
H
Terephthalyl
Terephthalyl
OEt
OMe
4t
4u
10
10
aIsolated yields.
were carried out by exposing the reactants to microwaves in a glass
round-bottom flask. The flask was connected with an air condenser, which
passed through a metallic tube to the side of the oven and was then connected
with the water reflux condenser outside the oven to minimize water
evaporation. It must be noted that the same reactions performed without
microwaves, even at 1008C, gave nonsignificant yields in 10 mins. The solu-
bilizing power of phase-transfer catalyst in water and the heating power of
microwaves can be combined effectively to enhance a number of reactions.
The terephthalaldehyde with b-ketoesters and ammonium acetate afford
the corresponding bis-substituted products (4t, 4u) in good yields (Scheme 2).
In conclusion, the present procedure of the synthesis of 1,4-dihydro-
pyridines in water using phase-transfer catalyst under microwave irradiation
provides an efficient and improved modification of Hantzsch’s reaction in
high yields and short reaction times. In addition, it is possible to apply the
tenets of green chemistry to the generation of biologically interesting Hantzsch

1,4-Dihydropyrdines
4353
Scheme 2.
products using aqueous medium approaches that are less expensive and less
toxic than those with organic solvents.
EXPERIMENTAL
Melting points are uncorrected. Infrared (IR) spectra were run on a Bruker
1
spectrometer and expressed in cm21 (KBr). H NMR spectra were recorded
on a Bruker AVMCE-300 MHz in CDCl3 solutions. High-resolution mass
spectra were obtained with a Micromass GCT TOF mass spectrometer.
A domestic microwave oven (SANYO EM-300S) was modified to suit the
reaction.
General Procedure for the Synthesis of 1,4-Dihydropyridines
Representative Procedure for 2,6-Dimethyl-3,5-Dicarbomethoxy-
4-Phenyl-1,4-Dihydropyridine (4a)
Benzaldehyde (5 mmol), methyl acetoacetate (10 mmol), ammonium
acetate (10 mmol), tetrabutyl ammonium bromide (2.5 mmol) [for entries 16
and 17 in Table 1, terephthalaldehyde (5 mmol), ethyl/methyl acetoacetate
(20 mmol), ammonium acetate (20 mmol), and tetrabutyl ammonium bromide
(2.5 mmol)] and water (5 mL) were placed in a flask in the center of the
microwave oven. The flask was connected with an air condenser that passed
through a metallic tube to the side of the oven and was then connected with
the water reflux condenser outside the oven. After irradiation for 10 min at
400 W, the mixture was cooled to room temperature and extracted with
ethyl acetate (2 ꢀ 15 mL). The organic layer was dried over magnesium
sulfate and evaporated. The residue was purified by column chromatography

4354
Salehi and Guo
on silica gel using petroleum/ethyl acetate (V/V 7 : 3) as the eluent.
1
The products were characterized by IR, H NMR, mass spectra (MS), and
their melting points.
4a: Mp 196–1988C. IR (KBr): n ¼ 3343, 3081, 3026, 2950, 1699,
1
1649 cm21. H NMR (CDCl3): d ¼ 2.34 (s, 6H), 3.64 (s, 6H), 5.00
(s, 1H), 5.58 (s, 1H), 7.12–7.25 (m, 5H). MS: m/z ¼ 301.13 (Mþ),
299, 267, 236, 224, 210, 192, 164, 77.
4b: Mp 210–2128C. IR (KBr): n ¼ 3349, 3005, 2953, 1704, 1650,
1
1528 cm21. H NMR (CDCl3): d ¼ 2.37 (s, 6H), 3.64 (s, 6H), 5.10
(s, 1H), 5.71 (s, 1H), 7.25 (t, 1H, J ¼ 7.89), 7.61 (m, 1H), 7.98 (m,
1H), 8.08 (t, 1H, J ¼ 1.84). MS: m/z ¼ 346.11 (Mþ), 344, 328, 327,
313, 297, 281, 224, 192, 152, 115, 43.
4c: Mp 186–1888C. IR (KBr): n ¼ 3348, 2948, 1696, 1650, 1625 cm21
.
1H NMR (CDCl3): d ¼ 2.33 (s, 6H), 3.64 (s, 6H), 3.75 (s, 3H), 4.93
(s, 1H), 5.56 (s, 1H), 6.74 (d, 2H, J ¼ 6.67). 7.16 (d, 2H, J ¼ 6.83).
MS: m/z ¼ 331.14 (Mþ), 329, 298, 272, 266, 265, 238, 224, 210,
196, 115, 77, 43.
4d: Mp 196–1988C. IR (KBr): n ¼ 3314, 3102, 2945, 1699, 1651,
1
1486 cm21. H NMR (CDCl3): d ¼ 2.38 (s, 6H), 3.64 (s, 6H), 4.96
(s, 1H), 5.62 (s, 1H), 7.15–7.21 (m, 4H). MS: m/z ¼ 335.09 (Mþ),
304, 270, 224, 192, 164, 43.
4e: Mp 192–1948C. IR (KBr): n ¼ 3344, 2951, 1698, 1651, 1492,
1
1434 cm21. H NMR (CDCl3): d ¼ 2.34 (s, 6H), 3.70 (s, 6H), 5.19
(s, 1H), 5.70 (s, 1H), 5.92 (d, 1H, J ¼ 3.21), 6.20 (dd, 1H, J ¼ 1.90,
1.70) 7.21 (d, 1H, J ¼ 1.66).
4f: Mp 190–1928C. IR (KBr): n ¼ 3323, 3101, 2951, 1681, 1649, 1620
1
1582 cm21. H NMR (CDCl3): d ¼ 2.32 (s, 6H), 3.61 (s, 6H), 5.35
(s, 1H), 5.60 (s, 1H), 7.09 (d, 1H, J ¼ 8.20), 7.26 (s, 1H), 7.29 (d,
1H, J ¼ 8.18). MS: m/z ¼ 369.05 (Mþ), 338, 334, 332, 300, 224, 192.
4g: Mp 230–2328C. IR (KBr): n ¼ 3329, 3001, 2953, 1681, 1650, 1611,
1589 cm21. 1H NMR (CDCl3): d ¼ 2.33 (s, 6H), 3.64 (s, 6H), 4.70 (s,
1H), 4.92 (s, 1H), 5.57 (s, 1H), 6.65 (d, 2H, J ¼ 6.60). 7.10 (d, 2H,
J ¼ 6.66).
4h: Mp 194–1968C. IR (KBr): n ¼ 3302, 3233, 3095, 2947, 1702, 1682,
1
1649 cm21. H NMR (CDCl3): d ¼ 2.31 (s, 6H), 3.60 (s, 6H), 5.39 (s,
1H), 5.61 (s, 1H), 7.03–7.38 (m, 5H). MS: m/z ¼ 335.09 (Mþ), 304,
298, 224, 192, 164, 127.

1,4-Dihydropyrdines
4355
4i: Mp 174–1768C. IR (KBr): n ¼ 3314, 3105, 2942, 1697, 1655,
1
1495 cm21. H NMR (CDCl3): d ¼ 2.27 (s, 3H), 2.33 (s, 6H), 3.64
(s, 6H), 4.96 (s, 1H), 5.62 (s, 1H), 7.00 (d, 2H, J ¼ 8.01). 7.14 (d,
2H, J ¼ 8.07). MS: m/z ¼ 315.14 (Mþ), 313, 281, 250, 224, 192,
152, 115, 43.
4j: Mp 176–1788C. IR (KBr): n ¼ 3336, 3021, 2949, 1698, 1650,
1
1493 cm21. H NMR (CDCl3): d ¼ 2.34 (s, 6H), 3.69 (s, 6H), 4.60
(d, 1H, J ¼ 4.74), 5.61 (brs, 1H), 6.16 (m, 1H), 7.15–7.33 (m, 5H).
MS: m/z ¼ 326.13 (Mþ), 325, 312, 295, 278, 262, 234, 224, 206,
192, 165, 152, 97, 85, 71, 57, 43.
4k: Mp 208–2108C. IR (KBr): n ¼ 3345, 3107, 3005, 2949, 1697, 1646,
1
1505, 1431, 1383 cm21. HNMR (CDCl3): d ¼ 2.85 (s, 6H), 3.72 (s,
2H), 3.93 (s, 6H), 8.70 (s, 1H). MS: m/z ¼ 225.10 (Mþ), 224, 223,
210, 192, 165, 164, 132, 120, 104, 77, 43.
4l: Mp 152–1548C. IR (KBr): n ¼ 3341, 3266, 3108, 2949, 1680,
1
1649 cm21. H NMR (CDCl3): d ¼ 0.94 (d, 3H, J ¼ 6.30), 2.27 (s,
6H), 3.71 (s, 6H), 3.77 (q, 1H, J ¼ 6.51), 5.52 (s, 1H). MS: m/
z ¼ 239.11 (Mþ), 224, 208, 192, 178, 164, 149, 120, 43.
4m: Mp 140–1428C. IR (KBr): y ¼ 3249, 2958, 2878, 1697, 1648,
1
1463 cm21. H NMR (CDCl3): d ¼ 0.80 (t, 3H, J ¼ 6.87), 1.18–1.30
(m, 4H), 2.28 (s, 6H), 3.71 (s, 6H), 3.89 (m, 1H), 5.54 (brs, 1H).
4n: Mp 122–1248C. IR (KBr): y ¼ 3352, 3092, 2952, 2868, 1698,
1
1652 cm21. H NMR (CDCl3): d ¼ 0.85 (d, 6H, J ¼ 6.48), 1.09 (m,
1H), 2.29 (s, 6H), 3.71 (s, 6H), 3.91 (m, 1H), 5.62 (brs, 1H).
4o: Mp 158–1608C. IR (KBr): n ¼ 3341, 2981, 1687, 1650, 1488 cm21
.
1H NMR (CDCl3): d ¼ 1.19 (t, 6H), 2.33 (s, 6H), 4.04 (m, 4H), 4.98 (s,
1H), 5.52 (s, 1H), 7.11–7.28 (m, 5H). MS: m/z ¼ 329.16 (Mþ), 327,
282, 254, 252, 236, 224, 210, 196, 180, 139.
4p: Mp 160–1628C. IR (KBr): n ¼ 3344, 3090, 2989, 2932, 1705, 1645,
1
1524, 1487 cm21. H NMR (CDCl3): d ¼ 1.19 (t, 6H), 2.36 (s, 6H),
4.03 (m, 4H), 5.09 (s, 1H), 5.66 (s, 1H), 7.34 (m, 1H), 7.62 (m, 1H),
7.98 (m, 1H), 8.11 (m, 1H). MS: m/z ¼ 374.14 (Mþ), 355, 327, 299,
281, 252, 224, 196, 150, 127, 77, 43.
4q: Mp 166–1688C. IR (KBr): n ¼ 3345, 2982, 1699, 1650, 1488 cm21
.
1H NMR (CDCl3): d ¼ 1.23 (t, 6H, J ¼ 7.11), 2.33 (s, 6H), 4.07 (m,
4H), 5.19 (s, 1H), 5.69 (s, 1H), 5.94 (d, 1H, J ¼ 3.18), 6.20 (dd, 1H,
J ¼ 1.86, 1.86), 7.21 (d, 1H, J ¼ 1.62). MS: m/z ¼ 319.14 (Mþ),
317, 290, 262, 246, 245, 218, 214, 174, 144, 115.

4356
Salehi and Guo
4r: Mp 128–1308C. IR (KBr): n ¼ 3344, 2962, 1697, 1642, 1492 cm21
.
1H NMR (CDCl3): d ¼ 0.96 (d, 3H, J ¼ 6.45), 1.27 (t, 6H, J ¼ 7.05),
2.26 (s, 6H), 3.82 (q, 1H, J ¼ 6.45), 4.12 (m, 4H), 5.45 (s, 1H). MS:
m/z ¼ 267.14 (Mþ), 265, 252, 236, 224, 220, 208, 196, 192, 178,
164, 150, 77, 43.
4s: mp 170–1728C. IR (KBr): n ¼ 3351, 3108, 2987, 2898, 1693, 1654,
1507 cm21. 1HNMR (CDCl3): d ¼ 1.30 (t, 6H, J ¼ 3.48), 2.19 (s, 2H),
3.26 (s, 6H), 4.43 (q, 4H, J ¼ 7.17), 8.70 (s, 1H).
4t: Mp 2828C (dec.). IR (KBr): n ¼ 3349, 2986, 2936, 1695, 1650, 1487,
1
1447 cm21. H NMR (CDCl3): d ¼ 1.07 (t, 12H, J ¼ 6.99), 2.22 (s,
12H), 3.91 (q, 8H, J ¼ 6.93), 4.77 (s, 2H), 6.95 (brs, 4H), 8.73 (s, 2H).
4u: Mp 2878C (dec.). IR (KBr): n ¼ 3346, 2950, 1703, 1650, 1484, 1460,
1
1433 cm21. H NMR (CDCl3): d ¼ 2.26 (s, 12H), 3.57 (s, 12H), 4.84
(s, 2H), 6.96 (brs, 4H), 8.86 (s, 2H).
ACKNOWLEDGMENT
This work was supported by the CAS, MOST, NSFC, and the University
of Science and Technology of China.
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Received in Japan June 16, 2004